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Primary IgA Nephropathy: Pathophysiology, Diagnosis, and Clinical Management.

Immunoglobulin A (IgA) nephropathy was first described in 1968 by Berger and Hinglais as a predominance of IgA deposition in the glomerular mesangium (Glasscock, Cohen, & Adler, 1996). IgA nephropathy, or Berger's disease, is recognized as the most frequent type of glomerulonephritis worldwide (D'Amico, 1987). The disease has been observed in all races with the highest incidence in Native Americans and the lowest incidence in North American blacks (Emancipator, 1998). IgA nephropathy usually occurs in the second and third decade of life and has male predominance (Glasscock et al., 1996). Up to 40% of patients with IgA nephropathy progress to end stage renal disease (ESRD) within 25 years. IgA nephropathy accounts for 10%-30% of all cases of ESRD (D'Amico, 1987).

The two types of IgA nephropathy, primary and secondary, are both characterized by mesangial deposition of IgA. Secondary IgA nephropathy occurs in patients with cirrhosis of the liver, mucosal diseases, hematologic diseases, and systemic autoimmune diseases. The majority of cases of secondary IgA nephropathy are benign and are not diagnosed until autopsy (Emancipator, 1998). This article discusses the pathophysiology, diagnosis, and clinical management of primary IgA nephropathy.

Pathophysiology

Immunoglobulins (Ig), a synonym for antibodies, are secreted by B lymphocytes in response to an antigen (Male, 1986). An antigen is any substance that is able to elicit an immune response. IgG, IgM, IgA, IgD, and IgE are the five classes of antibodies in humans. IgG accounts for 75% of the total serum Igs and provides protection against bacteria, fungi, and viruses. IgM is the major Ig expressed on the surface of B cells and is involved with the natural blood group antibodies. Activation of IgG production depends on IgM. IgE is present in trace amounts, yet has an important role in allergic responses. IgD, also present in trace amounts, has an unknown function (Stites & Ten, 1991). IgA, the predominant class of Igs in secretions of mucous membranes, is found in the saliva, tears, and bronchial, small intestine, and urinary tract secretions.

Igs are composed of parallel light and heavy polypeptide chains (see Figure 1). Each Ig has a constant region that is related to the Ig's ability to adhere to other structures and ability to activate the complement system. The variable region, which is different for each antibody, binds with a specific antigen (Guyton & Hall, 1996). The Ig chains are held together by disulfide bonds. An Ig dimer is formed when two antibodies join together; this dimer is joined by a polypeptide called the J-chain (see Figure 2).

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IgA1 and IgA2 are subclasses of IgA; both are primarily found in mucosal secretions. Patients often will report a recent mucosal infection, such as an upper respiratory infection, before development of symptoms of IgA nephropathy. As a result of the infection, production of IgA1 in the bone marrow and spleen increases. The IgA1 lacks the J-chain portion, preventing the transport of IgA1 into the mucosal secretions (Emancipator, 1998). Thus, IgA1 increases in the systemic circulation and is deposited into the glomerular mesangium. IgA2, however, does have the J portion and is transported into mucosal secretions. In IgA nephropathy IgA1 is found primarily in the mesangium and IgA2 in mucosal secretions.

Under normal conditions, IgA levels increase with a mucosal antigen-antibody interaction, and the mononuclear phagocyte system (MPS) (composed of neutrophils, monocytes, and macrophages) removes the IgA complexes from the circulation by phagocytosis (Emancipator, 1998; Glasscock et al., 1996). Normal removal of IgA by the MPS results in minimal or no glomerular injury. Mucosal infections can result in an abnormal immune response that involves IgA, IgG, and IgM. Their impaired removal by the MPS results in mesangial deposition and glomerular injury. IgA nephropathy primarily involves IgA deposits in the mesangium, but only 26% of patients have deposition of IgA alone. IgG and IgM deposits also occur in 37% and 13% of cases respectively, and the three coexist in 25% of cases (Emancipator, 1998)(see Figure 3).

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Although IgA nephropathy is known to be an immune complex disease, the exact pathogenesis is unknown (D'Amico, 1987). IgA nephropathy may develop because of the presence of consistently elevated levels of IgA and a defect in the MPS. Defects in the regulation of IgA production leads to increased IgA levels, which can not be removed by the MPS. This theory of increased production of IgA is supported by the finding that the tonsils of patients with IgA nephropathy have higher levels of IgA-bearing lymphocytes when compared to those without IgA nephropathy (D'Amico, 1987). IgA levels also may be increased secondary to dysfunction of the MPS, but it is unknown exactly why the MPS may have a defect. The presence of IgA itself may result in the impaired ability of phagocytes to uptake excess IgA (Emancipator, 1998).

The renal glomerulus is made up of endothelial cells, basement membrane, podocytes, and mesangial cells (see Figure 4). Some of the mesangial cells are phagocytes, while others are involved in glomerular filtration (Vander, 1995). The currently accepted theory for mesangial injury involves immune complex deposition in the mesangium (Emancipator, 1998). In IgA nephropathy, there are increased levels of IgA secondary to both increased IgA production and decreased IgA removal by the MPS. As a result, the excess IgA forms deposits as discrete granules in the glomerular mesangium. When IgA deposits in the mesangium, antigens bind to form immune complexes. The presence of the immune complexes results in functional changes in the mesangial cells. Hematuria is one result of these changes. Research also suggests that in response to IgA, the glomerulus synthesizes thromboxane, a vasoconstrictor, and its production exceeds that of prostaglandins (vasodilators). Therefore, mesangial IgA deposition results in glomerular vasoconstriction and a decrease in glomerular filtration rate (GFR) (Emancipator, 1998). Diagnosis and appropriate treatment of IgA nephropathy may reduce the severity of mesangial changes and vasoconstriction, subsequently preventing ESRD.

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Diagnostic Approach

When diagnosing IgA nephropathy, the clinician needs to consider data from the patient's history, physical examination, and laboratory studies. Differential diagnoses need to be considered also.

The patient's history often includes the recent occurrence of an upper respiratory infection. Patients will often present with a chief complaint of hematuria and flank pain. Hematuria is the presenting symptom in more than 75% of all patients and is eventually observed in more than 95% of patients (Emancipator, 1998). Macroscopic hematuria occurs 24-48 hours after an infection of the respiratory, gastrointestinal, or urinary tract and continues for a few hours to many days (D'Amico, 1987).

The physical examination may reveal no abnormal findings. Less than 10% of patients present with signs of acute glomerulonephritis, such as edema, hypertension, and hematuria (Galla, 1995). Laboratory data along with the patient's history are most beneficial for diagnosing IgA nephropathy. The urinalysis will reveal either macroscopic hematuria or microscopic hematuria with mild proteinuria. Microscopic hematuria with mild proteinuria occurs in 30%-40% of patients.

Serum complement levels in IgA nephropathy are often normal, even though there is glomerular deposition of complement proteins. Plasma IgA levels are increased in 30-50% of patients, but this finding alone is not sufficient to establish the diagnosis of IgA nephropathy (Galla, 1995).

A renal biopsy with immunofluorescent examination is required to confirm IgA nephropathy. A renal biopsy is indicated when there is progression of hematuria, 1 g or mote per day of protein excretion, increased serum creatinine, and hypertension (Neelakantappa, Gallo, & Baldwin, 1988). Although IgA, IgG, and IgM deposits may be found, IgA mesangial deposits are required to differentiate IgA nephropathy from other diagnoses (Julian, 1998). When evaluating the patient, the clinician must consider differential diagnoses, including acute postinfectious glomerulonephritis (APGN) and Henoch Schonlein purpura (HSP).

APGN often occurs in patients between the ages of 5 and 15 years old. A patient with APGN often will present with hematuria, edema, and hypertension. The hematuria will last for more than 1 year, whereas hematuria secondary to IgA nephropathy will rapidly resolve (Moudgil, Bagga, Ragini, & Jordan, 1998). The onset of signs and symptoms of APGN is similar to IgA nephropathy in that it is often preceded by an infection. A patient with APGN, however, experiences hematuria 1 to 2 weeks after the initial infection (D'Amico, 1987). A distinguishing characteristic of APGN is the presence of antistreptolysin O (ASO) antibodies and a depression in serum complement levels (hypocomplementemia). Renal biopsy is rarely indicated for diagnosis of APGN (Moudgil et al., 1998). If a renal biopsy is performed there will be glomerular immune deposits that appear dense (Cotran, Kumar, & Collins, 1999) (see Table 1).
Table 1
Differentiation of Acute Postinfectious Glomerulonephritis
and IgA Nephropathy

                                          Signs and Symptoms

Acute postinfectious glomerulonephritis   Hematuria 1-2 weeks after
                                          infection

                                          Edema

                                          Hypertension

                                          Positive antistreptolysin O
                                          (ASO) titer

                                          Hypocomplementemia

                                          Renal biopsy with dense
                                          glomerular immune deposits

IgA nephropathy                           Hematuria 24-48 hours after
                                          infection

                                          Flank pain

                                          Normal complement levels

                                          Increased plasma IgA levels

                                          Renal biopsy: Mesangial IgA
                                          deposition, possible IgG &
                                          IgM


A patient with HSP also will have mesangial deposits of IgA. Differentiation of the two diagnoses is based on the patient's history and physical examination. HSP occurs more frequently in children, and the patient will often present with signs and symptoms that involve the skin, intestines, or joints (Julian, 1998). Most patients with HSP present with skin lesions that resemble a purpuric rash, which is an important differentiation of IgA nephropathy from HSP.

Clinical Management

Treatment of IgA nephropathy and the prevention of ESRD are important aspects of management. Since the pathogenesis of IgA nephropathy is not completely understood, there is no accepted standard treatment regimen. Although some clinicians choose not to treat IgA nephropathy (Scheinman, Trachtman, Langman, & Chan, 1997), angiotensin converting enzyme (ACE) inhibitors, oral glucocorticoids, and fish oil are frequently used for IgA nephropathy management.

ACE inhibitors inhibit the enzyme that converts angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that increases the pressure within the glomerulus (Guyton & Hall, 1996). The desired result of ACE inhibitor use is a decrease in glomerular pressure and improved renal function by allowing dilation of the efferent arteriole of the glomerulus. Cattran, Greenwood, and Ritchie (1994) reported that ACE inhibitors are beneficial to patients with IgA nephropathy independent of their ability to control blood pressure. In another large scale, randomized controlled trial, ACE inhibitors were shown to reduce serum creatinine levels over 3 years by 50% in patients with insulin dependent diabetes mellitus (Matsusaka, Hymes, & Ichikawa, 1996). Even though ACE inhibitors may slow the progression of IgA nephropathy to ESRD, they have not been shown useful in the treatment of proteinuria related to IgA nephropathy.

The goal with oral glucocorticoids (e.g., prednisone) is to suppress the patient's systemic immune response. Prednisone also may reduce proteinuria, but does not alter the overall course of IgA nephropathy (Scheinman et al., 1997). Oral glucocorticoids, however, are not used to treat mild, stable, or progressive IgA nephropathy because of numerous side effects related to their prolonged use (Scheinman et al., 1997). Health care providers often choose not to include glucocorticoids in the treatment of IgA nephropathy due to the disadvantages of long-term use.

The use of fish oil in management of IgA nephropathy is controversial. Fish oils are high in omega-3 fatty acids, which may decrease immune complexes and triglycerides (Scheinman et al., 1997). The fatty acids also may prevent renal damage by inhibiting inflammation and thromboxanes while allowing prostaglandin synthesis (Emancipator, 1998). There is the possibility, however, that the accumulation of omega-3 fatty acids causes renal damage. Patients also may complain of gastrointestinal symptoms and a fishy taste when taking fish oil (Scheinman et al., 1997). Recent research suggests that the use of fish oil in the treatment of IgA nephropathy does slow progression to ESRD (Donadio et al., 1999).

Clinical management requires that the physician, nurse practitioner, and staff nurse work together to provide care for the patient. This requires all to have an understanding of the pathophysiology that is involved with IgA nephropathy. The nurse can educate the patient and answer questions that may arise about the pathophysiology and the prescribed regimen. Nurses must also encourage patients to follow the prescribed treatment plan even though immediate results are not evident to the patient.

Prognosis

A patient who has IgA nephropathy may have no complications or may progress to ESRD. Ten percent of patients will have sustained remission, and 60% to 70% will have a course of recurrent symptoms. Of this 60% to 70% of patients, approximately 30% will maintain a normal GFR, and another 30% will develop ESRD and require dialysis or transplantation (Emancipator, 1998).

Prognosis is based on the patient's clinical course. There is an increased risk of progression to ESRD if the patient develops heavy proteinuria (1 g or more per 24 hours), hypertension, decreased GFR, a serum creatinine greater than 1.4 mg/dl, and does not have gross hematuria (Emancipator, 1998). Patients who experience hematuria tend to have a slower progression to ESRD. It is proposed that hematuria reflects the glomeruli's ability to cope with hemodynamic changes, which predicts the glomeruli's ability to cope with IgA deposits (Daniel et al., 2000). Recent data suggest that tubular lesions provide the best insight into prognosis. The amount of tubular lesions can reflect the degree of interstitial processes that are able to damage normal glomeruli (Daniel et al., 2000).

Summary

Since the initial description of IgA nephropathy by Berger and Hinglais in 1968, IgA nephropathy has become recognized as the most frequent cause of glomerulonephritis in the world. The pathogenesis of IgA nephropathy is not well understood. It is believed IgA production increases in response to antigens, and the MPS is unable to remove the excess IgA. As a result, IgA deposits are formed in the mesangium and renal damage ensues. Patients will frequently have elevated serum IgA levels, but a renal biopsy is essential to confirm diagnosis of IgA nephropathy. Hypertension and proteinuria must be treated to prevent or slow progression to ESRD. Although clinicians do not agree on treatment, the collaborative management often involves the use of an ACE inhibitor or oral glucocorticoids or both. There may also be benefits to using fish oil. Until the exact pathogenesis of IgA nephropathy is known, the clinical management will continue to be debated.

References

Cattran, D.C., Greenwood, C., & Ritchie, S. (1994). Long-term benefits of angiotensin-converting enzyme inhibitor therapy in patients with severe immunoglobulin A nephropathy: A comparison to patients receiving treatment with other antihypertensive agents and to patients receiving no therapy. American Journal of Kidney Diseases, 23, 247-254.

Cotran, R.S., Kumar, V., & Collins, T. (1999). Pathologic basis of disease (underlined) (6th ed.) (pp. 930-996). Philadelphia: W.B. Saunders Company.

D'Amico, G. (1987). The commonest glomerulonephritis in the world: IgA nephropathy. Quarterly Journal of Medicine, 64, 709-727.

Daniel, L., Saingra, Y., Giorgi, R., Bouvier, C., Pellissier, J.F., & Berland, Y. (2000). Tubular lesions determine prognosis of IgA nephropathy. American Journal of Kidney Diseases, 35, 13-20.

Donadio, J.V., Grande, J.P., Bergstralh, E.J., Dart, R.A., Larson, T.S., & Spencer, D.C. (1999). The long-term outcome of patients with IgA nephropathy treatment with fish oil in a controlled trial. Journal of the American Society of Nephrology, 10, 1772-1777.

Emancipator, S.N. (1998). IgA nephropathy and Henoch-Schonlein syndrome. In J.C. Jennette, J.L. Olson, M.M. Schwartz, & F.G. Silva (Eds.), Heptinstall's pathology of the kidney (5th ed.) (pp. 479-539). Philadelphia: Lippincott-Raven Publishers.

Galla, J.H. (1995). IgA nephropathy. Kidney International, 47, 377-387.

Glasscock, R.J., Cohen, A.H., & Adler, S.G. (1996). Primary glomerular diseases. In B.M. Brenner (Ed.), The kidney (5th ed.) (pp. 1301-1310). Philadelphia: W.B. Saunders Company.

Guyton, A.C., & Hall, J.E. (1996). Textbook of medical physiology (9th ed.) (pp. 449-450). Philadelphia: W.B. Saunders Company.

Julian, B.A. (1998). IgA nephropathy and related disorders. In A. Greenberg (Ed.), Primer on kidney diseases (2nd ed.) (pp. 170-175). San Diego: Academic Press.

Male, D. (1986). Immunology. St. Louis: C.V. Mosby Publishers.

Matsusaka, T., Hymes, J., & Ichikawa, I. (1996). Angiotensin in progressive renal diseases: Theory and practice. Journal of the American Society of Nephrology, 7, 2025-2043.

Moudgil, A., Bagga, A., Ragini, F., & Jordan, S.C. (1998). Poststreptococcal and other infection-related glomerulonephritides. In A. Greenberg (Ed.), Primer on kidney diseases (2nd ed.) (pp. 193-199). San Diego, CA: Academic Press.

Neelakantappa, K., Gallo, G.R., & Baldwin, D.S. (1988). Proteinuria in IgA nephropathy. Kidney International, 33, 716-721.

Scheinman, J.I., Trachtman, H., Lin, C.Y., Langman, C.B., & Chan, J.C. (1997). IgA nephropathy: To treat or not to treat? Nephron, 75, 251-258.

Stites, D.P., & Ten, A.I. (1991). Basic human immunology (1st ed.). Norwalk, CT: Appleton & Lange.

Vander, A.J. (1995). Renal physiology (5th ed.). New York: McGraw Hill Book Company.

Betsy Jane Staples, MSN, RN, ACNP, is a recent graduate of the acute care nurse practitioner nephrology focus specialty at Vanderbilt University School of Nursing, Nashville, TN.

Acknowledgment: The author wishes to thank Dr. Larry E. Lancaster for his positive influence, intelligence, patience, and guidance in preparation of this manuscript.
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Author:Staples, Betsy Jane
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Apr 1, 2001
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